5

Vol. 3. No. 1 JanuaryMarch 2012

Research Report

THE CHANGING CLINICAL PERFORMANCE OF DENGUE VIRUS

INFECTION IN THE YEAR 2009
Soegeng Soegijanto1,2,3, Helen Susilowati3, Kris Cahyo Mulyanto3, Eryk Hendrianto3 and Atsushi Yamanaka4
1
Department of Child Health Dr. Soetomo Hospital Surabaya
2
Medical Faculty of Airlangga University Surabaya
3
Institute of Tropical Disease Center Airlangga University
4
Kobe University Graduate School of Medicine

ABSTRACT
Background: Dengue (DEN) virus, the most important arthropod-borne human pathogen, represents a serious public health
threat. DEN virus is transmitted to humans by the bite of the domestic mosquito, Aedes aegypti, and circulates in nature as four distinct
serological types DEN-1 to 4). The aim of Study: To identify Dengue Virus Serotype I which showed mild clinical performance in five
years before and afterward showed severe clinical performance. Material and Method: Prospective and analytic observational study
had been done in Dr. Soetomo Hospital and the ethical clearance was conduct on January 01, 2009. The population of this research
is all cases of dengue virus infection. Diagnosis were done based on WHO 1997. All of these cases were examined for IgM & IgG anti
Dengue Virus and then were followed by PCR examination to identify Dengue Virus serotype. Result and Discussion: DEN 2 was
predominant virus serotype with produced a spectrum clinical illness from asymptomatic, mild illness to classic dengue fever (DF) to the
most severe form of illness (DHF). But DEN 1 usually showed mild illness. Helen at al (20092010) epidemiologic study of Dengue Virus
Infection in Health Centre Surabaya and Mother and Child Health Soerya Sidoarjo found many cases of Dengue Hemorrhagic Fever
were caused by DEN 1 Genotype IV. Amor (2009) study in Dr. Soetomo Hospital found DEN 1 showed severe clinical performance of
primary Dengue Virus Infection as Dengue Shock Syndrome two cases and one unusual case. Conclusion: The epidemiologic study of
Dengue Virus Infection in Surabaya and Sidoarjo; in the year 2009 found changing predominant Dengue Virus Serotype from Dengue
Virus II to Dengue Virus 1 Genotype IV which showed a severe clinical performance coincident with primary infection.

Key words: Changing Clinical Performance, Dengue Infection.

INTRODUCTION severe form of illness, dengue hemorrhagic fever (DHF).

Dengue (DEN) virus, the most important arthropod-
borne human pathogen, represents a serious public health
threat. DEN virus is transmitted to humans by the bite of the
domestic mosquito, Aedes aegypti, and circulates in nature
as four distinct serological types DEN-1 to 4. DEN virus
has been recognized in over 100 countries, and 2.5 billion
people live in areas where DEN virus is endemic.16
Dengue, an emerging arboviral and arthropod borne
disease, is a major cause of morbidity throughout the tropical
and sub-tropical regions of the world.1 Dengue virus (DV)
infection with any 1 of 4 serotypes produces a spectrum
of clinical illness, ranging from an asymptomatic or mild
febrile illness to classic dengue fever (DF) to the most
DHF is characterized by plasma leakage and a hemorrhagic
diathesis near the time of differences, typically after 5 days
of fever.2 In severe DHF, morbidity and mortality are the
result of hypotension and shock, at times accompanied by
severe coagulation abnormalities and bleeding. Since early
hospitalization and careful supportive care can reduce the
case-fatality rate of DHF, the rapid identification of patients
at risk for developing DHF is desirable in regions where
DV is endemic.
Dengue hemorrhagic fever is one of the important health
problem in Indonesia, although the mortality rate has been
decreased but many dengue shock syndrome cases is very
difficult to be solving handled. Natural course of dengue
virus infection is very difficult to predict of the earlier time
6 Indonesian Journal of Tropical and Infectious Disease, Vol. 3. No. 1 JanuaryMarch 2012: 59

of severity occur; It is may be due to the new variant of Serotype DEN 1: there ware only 3 cases (see table 3)
dengue virus that infect a child could be severe and can not consisted of 2 cases had age 1-4 years and 1 had age 514
be identified earlier. years. They showed a severe clinical performance as DSS
Previous study show that some of DEN 2 and DEN 3 2 cases and 1 case as unusual case (see table 1).
virus cases could show a clinical performance of severe
dengue virus infection such as dengue shock syndrome.
Based on Halstead hypothesis, the severe dengue virus Table 1. Distribution of Serotype and Clinical Performance of
infection could be correlated with secondary infection. The Dengue Virus Infection
infant cases show a severe clinical manifestation. Clinical Performance & Diagnostic
In Thailand and Cuba, many cases of dengue virus
Serotype DF DHF DSS UNUSUAL Total
infection were identified as secondary infection and some
DEN 1 0 0 2 1 3
of them showed dengue shock syndrome, but this case did
DEN 2 30 26 7 2 65
not found in other countries. Moren (1980) found that the
DEN 3 1 0 1 0 2
differences of growing dengue virus in monocyte could
be a predictor of severity or mild cases for dengue virus DEN 4 0 0 0 0 0
infection. Total 31 26 10 3 70
The first outbreak of DHF in Indonesia was reported Kruskal-Wallis: p = 0,03*
in Java Island in 1968, all types (Den VI-4) were isolated * = significant (p < 0,05)
from patient in Jakarta in 19731974. Indonesia has
approximately 100.000 annual dengue cases. Since then
Table 2. Distribution of Clinical Performance of Dengue Virus
some outbreak in other cities and island were reported and Infection
the type of circulating DEN virus varies in each province
and island. Based on Setiati TE et al (2006), recently Clinical Performance & Diagnostic
predominant type as follow: Jakarta DEN V3; Palembang Type of
DF DHF DSS UNUSUAL Total
DEN V3; Bandung DEN V2; Manado DEN V1; Merauke Infection
DEN V3; Yogyakarta DEN V3. Primary 16 7 1* 2 26
In the year 2009, Dengue Virus Team of Institute Secondary 15 19 9 1 44
Tropical Disease had done epidemiologic study in Total 31 26 10 3 70
Surabaya.
Mann-Whitney; p = 0,035*
* = significant (p < 0,05)
MATERIAL & METHOD
Serotype DEN 1 was usually mild case but in this study
Prospective and analytic observational study had been 1 case showed a severe clinical performance as DSS and
done in Dr. Soetomo Hospital and the ethical clearance identified as primary infection (see table2).
was conduct on January 01, 2009. The population of
this research is all cases of dengue virus infection that in
Tropical ward of children, diagnosis were done based on Table 3. Distribution of Primary and Secondary infection
WHO 1997. Cases of dengue virus infection were collected and Serotype that were correlated with clinical
Performance of Dengue Virus Infection
& involving in research based on inform concern. All of
these cases were examined for IgM & IgG anti dengue Clinical Performance & Diagnostic
virus and then followed by PCR examination to identify Type of
dengue virus serotype. DF DHF DSS UNUSUAL Total
Infection
Blood examination should be done everyday. X-Ray Primary
examination were also done base on clinical performance of DEN 1 0 0 1* 0 1
Pleural Effusion & Ascites. Data of all cases dengue virus DEN 2 16 7 0 2 25
infection should be analyze using method of Kruskal Walles
DEN 3 0 0 0 0 0
& Mann Whitney and Regression Logistic multivariet.
DEN 4 0 0 0 0 0
Total 16 7 1 2 26
RESULT & ANALYSIS Secondary
DEN 1 0 0 1 1 2
150 cases of primary and secondary of dengue virus DEN 2 14 19 7 0 40
infection were studied. Dengue virus was isolated from vero DEN 3 1 0 1 0 2
cell and 120 samples have positive CPE. 70 samples were DEN 4 0 0 0 0 0
found as serotype by doing RT-PCR examination. Total 15 13 9 1 44
Soegijanto et al.: The Changing Clinical Performance of Dengue Virus 7

The second case of DEN 1 was identified as secondary
dengue virus infection and the third case was an unusual
case which showed secondary of dengue virus infection (see
table 3). Based on Yamanaka this serotype DEN 1 might be
have genotype IV or mention as DEN 1 genotype IV.
DISCUSSION
Aryati (2005), Fedik (2007), had done an epidemiologic
study of dengue hemorrhagic fever cases this in Surabaya,
found that DEN virus 2 was a predominant types.
The study in Health Center of Surabaya DEN V2 was
predominant in Surabaya (see table 4).
All of them showed clinical manifestation of dengue
virus infection with produces a spectrum of clinical illness,
ranging from an asymptomatic or mild febrile illness to
classic dengue fever (DF) to the most severe form of illness
as dengue hemorrhagic fever (DHF). DHF is characterized
by plasma leakage and a hemorrhagic diathesis near the
time of differences, typically after 5 days of fever (2). Most
of them showed severe dengue hemorrhagic fever as the
result of hypotension and shock, at the times accompanied
by severe coagulation abnormalities and bleeding. Since
early hospitalization and careful supportive care can reduce
the case-fatality rate of DHF, the rapid identification of
patients at risk for developing DHF is desirable in regions
where DV is endemic. On the year 2007 13% (7 cases)
showed very severe clinical performance of dengue virus
infection due to combining virus of DEN 2 and DEN 3
infected in one host of dengue hemorrhagic fever case that
could induce viremia.
But based on epidemiologic study in Surabaya &
Sidoarjo on 2009 and 201027 found many cases of dengue
hemorrhagic fever were caused by virus DEN V1 (see
table 5).
The clinical performance of cases Dengue Virus
Infection who came in health center of Surabaya in
year 2008 with 2169 cases showed clinical performance
of Dengue Fever 87% and 10% Dengue Hemorrhagic
Fever and Dengue Shock Syndrome and 3% unusual
manifestation. In the year 2009 with 2268 cases Dengue
Virus Infection showed clinical performance of Dengue
Fever 71.5% and Dengue Hemorrhagic Fever and Dengue
Shock Syndrome 28% and unusual cases of Dengue Virus
Infection 0.5% (see table 6).
This finding supported study of mosquito bites to some
peoples live surrounding Dengue Hemorrhagic cases who
had been admitted in hospital (see table 7).

Table 4. Prevelance Dengue Virus Infection based on serotype virus that was found in Surabaya on the year 20032005, 2007,
2008.

Year DEN V1 DEN V2 DEN V3 DEN V4 D2+D3 Total

20032005 0 20 (80%) 4 (16%) 1 (4%) 25
2007 0 46 (87%) 0 0 13% 53
2008 0 20 (100%) 0 0 20

Table 5. Prevalence Dengue Virus Infection in Surabaya & Sidoarjo in 20092010.

Year DEN V1 DEN V2 DEN V3 DEN V4 Total

2009 79 (87%) 6 (6.5%) 0 6 (6.5%) 91
2010 (JanFeb) 27 (100%) 0 0 0 27

Table 6. Clinical performance of dengue virus infection in Health Centre of Surabaya

Year Total Patients Dengue Fever DHF + DSS Unusual

2008 2169 1890 (87%) 216 (10%) 63 (3%)
2009 2268 1601 (71,5%) 656 (28%) 11 (0,5%)

Table 7. Virus Isolation from Mosquito

2008
Mosquito
Total Pool CPE Immune staining PCR Sequencing
Ae.aegypti 271 12 2 Dengue D2 D2
Cx.quinquefasciatus 336 10 4 Dengue D2 D2
Cx.tritaeniorhynchus 131 3
Cx.vishnui 71 1
Cx.pseudovishnui 42 1 1 Dengue D2 D2
8 Indonesian Journal of Tropical and Infectious Disease, Vol. 3. No. 1 JanuaryMarch 2012: 59
Table 8. Virus Isolation from Mosquito
Mosquito
Total Pool CPE
Ae.aegypti 1784 45 13
Cx.quinquefasciatus 74 4 1
Table 7 supported previous epidemiologic study that
found DEN V2 as predominant types in the year 2008 but
table 8 supported epidemiologic study in the year 2009
found DEN V1 as predominant types. The study in Dr.
Soetomo hospital since January 1, 2009 as followed DEN
1 showed clinical performance of Dengue Shock Syndrome
2 cases and unusual case with total 3 cases, DEN 2 were
found clinical performance of 30 cases Dengue Fever, 26
Dengue Hemorrhagic Fever 7 Dengue Shock Syndrome
and 2 unusual cases, with total 65 cases. DEN 3 were
found clinical performance of Dengue Fever 1 case Dengue
Shock Syndrome 1 case, with total 2 cases. Den 4 virus
was not found. The differences of result were found due to
the differences of population of study. But DEN V1 were
always found in this study.27
Virus isolation from mosquito bites showed DEN V1
has been isolated and identified on DEN 1 Genotype IV,
it was new variant virus that correlated with phylogenetic
Dengue Virus came from Beijing which had severe clinical
performance of Dengue Virus Infection.
Figure 1. Phylogenetic Dengue Virus in The World
In the year 2009 we have many experience to care
severe performance of Dengue Virus Infection with
unusual manifestation that could not followed WHO criteria
1997. More cases showed criteria for severe dengue virus
infection, as followed: Severe plasma leakage (leading to:
shock/DSS, Fluid accumulation with respiratory distress),
Severe bleeding (as evaluated by clinician), Severe organ
involvement (Liver: AST or ALT > = 1000, CNS: Impaired
consciousness, Heart and other organ). Therefore for
managing the unusual dengue virus infection we should
followed new WHO criteria diagnosis and classification
of cases as followed.
During three decades, the World Health Organization
(WHO) has recognized and recommended the classification
of dengue in: dengue fever (DF) and dengue hemorrhagic
20092010
Immune staining PCR Sequencing
Dengue D1 D1
Dengue D1
Figure 2. Suggested dengue case classification and levels of
severity. Dengue guidelines for diagnosis, treatment,
prevention, and control. World Health Organization,
UNICEF, UNDP. New Edition 2009
fever (DHF) with or without dengue shock syndrome
(DSS). 6 However in some severe cases the clinical
manifestations sometimes doesn't fit to these definition
and classification. In this WHO recommendation clinical
manifestation in DF are mild form than DHF/DSS, but
in this case DF with severe hemorrhagic manifestation
and that may be life threatening. Dengue can also express
itself by means of the so-called "atypical" forms or unusual
manifestation.1,5 These unusual clinical manifestations may
delay recognition of potentially severe disease.
Lately, several publications that appeared worldwide
emphasize the need to revise the classification of severe
dengue.1 One of the revised dengue classification proposed
by DENCO (Dengue Control) has been applied and studied
in several countries in Asia and Latin America with good
result.1,7 The DENCO study concluded that 18 to 40% of
the cases could not be classified by means of the current
WHO Classification, and over 15% of unusual cases with
shock could not be classified as severe cases of dengue
either, since they did comply with some of the criteria to
be regarded as a case of DHF/DSS.1,7
The pathogenesis of bleeding in DF is poorly understood.
Thrombocytopenia may enhance the risk, but the primary
cause of bleeding is unknown. Limited data suggest that
activation of coagulation and fibrinolysis play role in the
pathogenesis (srichaikul). An imbalance in the regulation
of coagulation and fibrinolysis, as in disseminated
intravascular coagulation syndrome (DIC), in conjunction
with the characteristic thrombocytopenia may contribute
to the bleeding tendency in DF.
In the year 2009, the study found that DEN V1 genotype
IV showed a severe clinical performance. Of a primary
dengue virus infection. This study supported to Gubler
Soegijanto et al.: The Changing Clinical Performance of Dengue Virus
hypothesis which gave information that a new virulent
variant DEN V1 can cause a severe clinical performance
of dengue virus infection.
SUMMARY
The epidemiologic study of Dengue Virus infection in
Surabaya. In the year 2009 found a changing predominant
Dengue Virus from Dengue Virus 2 to Dengue Virus 1
genotype 4 which showed a severe clinical performance
coincident with primary infection.
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